Biodegradable block copolymeric compositions for drug delivery

ABSTRACT

An improved drug delivery composition and method of use is disclosed. The composition comprises one or more biodegradable block copolymer drug carriers; and a reconstitution enhancing and enabling agent comprising polyethylene glycol (PEG), a PEG derivative or a mixture of PEG and a PEG derivative. The composition can be administered as is or after being be dissolved or rapidly reconstituted in an aqueous vehicle to afford a homogeneous solution or uniform colloidal systems.

REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation-in-part of application Ser.No. 10/167,768 filed Jun. 11, 2002.

FIELD OF THE INVENTION

[0002] The present invention relates to a composition for drug delivery.More specifically, the present invention relates to a copolymericcomposition comprising a liquid polyethylene glycol (PEG), a PEGderivative or a mixture of PEG and PEG derivative; and a biodegradableblock copolymeric drug carrier. Particularly, this invention relates tocompositions comprising a polyethylene glycol (PEG), PEG derivatives, ora mixture of a PEG and a PEG derivative, and biodegradable ABA, BAB andAB type block copolymers that are based on biodegradable hydrophobicpolyester or poly(ortho ester) A blocks and hydrophilic polyethyleneglycol (PEG) B blocks.

BACKGROUND OF THE INVENTION

[0003] Biodegradable polymers have been used as surgical sutures, wounddressings, and as drug delivery systems. Among them, polylactide (PLA),polyglycolide (PGA) and their copolymers (PLGA) have attracted the mostattention. One example of a biodegradable polymeric drug delivery systemis a system wherein a drug is contained in a biodegradable polymermatrix that is surgically implanted, which is a big disadvantage. In theform of injectable drug delivery systems, polymeric microspheres andnanospheres are known in the art. Commercially available drug deliveryformulations based on PLGA microspheres include Lupron Depot® andNutropin Depot®. Microsphere and nanosphere systems have disadvantagesin that they require special and complex preparation methods.Unfortunately, manufacturing microsphere and nanosphere dosage formsrequires use of toxic or dangerous solvents (e.g., methylene chloride,ethyl acetate) and elaborate procedures (e.g., double emulsions, orcryogenic spraying techniques). The batch size is usually small and thecost is high. In addition, since PLGA biodegradable polymers used canonly be dissolved in organic solvents their preparation requires the useof such solvents which are foreign and harmful to the human body, andcannot be completely removed during manufacture by any known method.Furthermore, some drugs such as peptides and proteins may lose theirpharmacological activity after contact with organic solvents.

[0004] An improvement to the aforementioned drug delivery systems is anin situ formed depot based on PLGA as disclosed in U.S. Pat. No.5,599,552. In that system, PLGA is dissolved in water-soluble organicsolvent(s), such as N-methyl-2-pyrrolidone, and the drug is eithersuspended or dissolved in this polymeric solution. The solution can beinjected subcutaneously to form an in situ depot to trap the drug in thepolymer that precipitates as the organic solvent diffuses away. However,the drawback is the requirement for an organic solvent that is used todissolve the biodegradable PLGA polymer. Organic solvents, such asN-methyl-2-pyrrolidone, are foreign to the human body and can causeunwanted side effects both acutely and chronically.

[0005] U.S. Pat. No. 5,543,158 discloses nanoparticles or microparticlesformed from a water-insoluble block copolymer consisting essentially ofpoly(alkylene glycol) and poly(lactic acid). The molecular weight of theblock copolymer is high and the copolymer is insoluble in water. In thenanoparticle or microparticle, the biodegradable moieties of thecopolymer are in the core of the nanoparticle or microparticle and thepoly(alkylene glycol) moieties are on the surface of the nanoparticle ormicroparticle in an amount effective enough to decrease uptake of thenanoparticle or microparticle by the reticuloendothelial system.Nanoparticles are prepared by dissolving the block copolymer and drug inan organic solvent, forming an o/w emulsion by sonication or stirring,and collecting the nanoparticles containing the drug followingprecipitation.

[0006] Currently there are few synthetic or natural polymeric materialsthat can be used for the controlled delivery of drugs, including peptideand protein drugs, because of strict regulatory compliance requirementssuch as biocompatibility, low toxicity, having a clearly defineddegradation pathway, and safety of the polymers and degradationproducts. The most widely investigated and advanced biodegradablepolymers in regard to available toxicological and clinical data are thealiphatic poly(α-hydroxy acids), such as poly(D-, L- , or D, L- lacticacid) (PLA), poly(glycolic acid) (PGA) and their copolymers (PLGA).These polymers are commercially available and are presently used asbioresorbable sutures and in biodegradable microsphere drug deliverysystems. FDA-approved microsphere systems for controlled release ofleuprolide acetate (Lupron Depot™) and human growth hormone (NutropinDepot™) are based on PLGA copolymers. Based on this history of use, PLGAcopolymers have been the materials of choice in the initial design ofparenteral controlled release drug delivery systems using abiodegradable carrier.

[0007] Even though there has been some limited success, biodegradableblock copolymers that are based on biodegradable polyester or poly(orthoester) and polyethylene glycol (PEG) blocks, when used as drug carriers,present problems that are associated with their physicochemicalproperties and attendant methods of fabrication. For example,biodegradable block copolymers are, by design, not stable in aqueousenvironments although shelf-lives of several years can be achieved whenthey are stored frozen. However, elimination of cold storagerequirements would be advantageous in most instances. It is alsodesirable to gain further advantages related to rapid dissolution ofneat block copolymers into aqueous vehicles at normal or ambient roomtemperature conditions. Rapid dissolution of the block copolymerspermits reconstitution at time-of-use to occur, which in turn permitsroom temperature storage of neat block copolymers. Known water solubleblock copolymers are slow to dissolve in water, often requiring severalhours for complete dissolution to occur. Compositions that showaccelerated dissolution kinetics are desired.

[0008] Some drugs, such as proteins, are stable in aqueous solutions foronly short periods. To compensate for this short-term stability, thesedrugs are commonly formulated as dry cakes and powders that can bestored under water-free conditions for much longer periods. Immediatelyprior to administration the dry cake or powder is reconstituted with anaqueous vehicle. Thus the situation is frequently encountered where itis desirable to have both the drug and the block copolymer drug deliverysystem formulated in reconstitutable forms. To be facile, it is criticalthat reconstitution, i.e., dissolution of the block copolymers and drugbe completed in a short period.

[0009] U.S. Pat. No. 5,384,333 discloses an injectable drug deliverycomposition in which a pharmacologically active substance is containedin a copolymer comprising a hydrophilic part and a hydrophobic part.However, the composition has to be heated to a relatively hightemperature such as 38° C. to 52° C., immediately before use and it isdifficult to uniformly distribute the drug in the polymeric composition.U.S. Pat. No. 5,612,052 discloses a block copolymer composition thatwhen contacted with water forms a hydrogel. However, the drugincorporated in this composition is rapidly released. U.S. Pat. No.5,599,552 discloses a composition wherein a water-insolublebiodegradable thermoplastic polymer is dissolved in a water-miscibleorganic solvent, and the resulting composition can be implanted where itthen undergoes a phase transition when in contact with water or bodyfluids. However, the drawback is that it is difficult to use because amono-molecular organic solvent is used to dissolve the biodegradablethermoplastic polymer. Most mono-organic solvents, such asN-methy-2-pyrrolidone, ethyl lactate, dimethylsulfoxide, etc., causeside effects such as cell dehydration and tissue necrosis, etc. and theymay also cause severe pain at the application sites.

[0010] U.S. Pat. No. 5,607,686 discloses a liquid polymeric compositionprepared by mixing a hydrophilic liquid polymer, instead of amono-molecular organic solvent, with a water-insoluble hydrophobicpolymer. When contacted with water the composition undergoes a phasetransition and forms an implant and thus it does not cause a the rapidvolume reduction and it has no special side effects due to the goodcyto-compatibility of the low molecular weight polyethylene oxide.However, the water-insoluble hydrophobic polymers used are notbiodegradable. In addition, the preparation of the composition requiresheating to about 80° C. in order to achieve uniform mixing of thewater-insoluble hydrophobic polymer and the hydrophilic liquid polymer.Therefore, this system may be suitable to use for adherence preventionand wound protection without any physiologically active substance, butit is not suitable for delivery of physiologically active substances,particularly peptide or protein medicines because peptide and proteinmedicines lose their activities at high temperatures. Furthermore,protein medicines are water soluble, thus it is very difficult touniformly incorporate them into the composition. In addition, it is notdisclosed in this patent how the drugs or physiologically activesubstances can be uniformly incorporated in the polymeric composition.Particularly, although polylactide, polyglycolide and their copolymerscan be mixed with polyethylene glycol at high temperatures of 80° C. inorder to obtain a uniform composition, the composition undergoes phaseseparation when it stands for a long period of time due the loweredaffinity of the polylactide, the polyglycolide or their copolymers withpolyethylene glycol. Therefore, it is very difficult to maintain auniform composition.

[0011] Sterilization steps are necessary in the preparation of implantformulations. Existing sterilization methods are unsuitable forsustained drug delivery formulations due to properties of the implantcompositions or because the methods are uneconomical or too complicated.For example, it is almost impossible to prepare a uniform solution bymixing a drug, a water-insoluble biodegradable polymer and a hydrophilicpolymer. Therefore, the composition cannot be sterilized by simplemethods such as membrane filtration. Furthermore, although theformulation may be prepared under sterilize conditions, such methods arevery expensive to the extent that the practicability of the preparationmay be lowered.

[0012] Therefore, there is a need for a biodegradable drug deliverycomposition that is a flowable liquid or can be rapidly reconstituted inan aqueous vehicle to afford a homogeneous true solution or uniformcolloidal system in order to be easily prepared and administered toprovide improved drug delivery. Accordingly, the present inventionrepresents improved drug delivery compositions that minimize or are freeof the problems mentioned above.

SUMMARY OF THE INVENTION

[0013] The present invention provides biodegradable compositions fordrug delivery and is a flowable liquid or can be rapidly reconstitutedin an aqueous vehicle to afford a homogeneous solution or uniformcolloidal system, and methods of use thereof for preparing apharmaceutically effective formulation for delivery of drugs.

[0014] The present invention also provides a method for preparing thebiodegradable drug delivery composition and a method for effectivelyadministering such a composition to warm blooded animals. The drugdelivery composition of the present invention can be administereddirectly to a warm blooded animal without an aqueous vehicle, or can beadministered after being rapidly reconstituted in an aqueous vehicle toafford a homogeneous solution or uniform colloidal system. Theadministration can be done by any functional means such as parenteral,ocular, inhalation, transdermal, vaginal, buccal, transmucosal,transurethral, rectal, nasal, oral, peroral, pulmonary, topical or auraland any other means of administration that may be compatible with thepresent invention.

[0015] The composition of the present invention comprises: 1) one ormore biodegradable block copolymer drug carriers comprising A-B, A-B-Aor B-A-B block, wherein the A block is a biodegradable polyester orpoly(ortho ester) and the B block is polyethylene glycol (PEG) and theweight percentage of the A block is between 20% to 99%; and 2) apolyethylene glycol (PEG), a PEG derivative, or a mixtures of PEG and aPEG derivative, wherein the biodegradable drug carrier is soluble in theliquid PEG and/or PEG derivatives. The weight averaged molecular weightof the biodegradable block copolymer of the present invention ispreferably within the range of 1,000 to 100,000 Daltons, more preferablywithin the range of 1,000 to 50,000 Daltons and most preferably withinthe range of 1,000 to 15,000 Daltons. Preferably, the weight percentageof the hydrophobic A block in the biodegradable block copolymer isbetween 20% to 99%, more preferably 20-85%.

[0016] One embodiment of the present invention is a compositioncomprises: 1) one or more biodegradable block copolymer drug carrierscomprising A-B, A-B-A or B-A-B block copolymers, wherein the A block isa biodegradable polyester or poly(ortho ester) and the B block ispolyethylene glycol (PEG), and 2) a polyethylene glycol (PEG), a PEGderivative, or a mixtures of PEG and a PEG derivative, wherein at leastone of the biodegradable block copolymers is soluble in an aqueoussolution and miscible with the PEG and/or PEG derivatives. Preferably,the biodegradable block copolymer drug carriers have a total molecularweight of 2000 to 8000 Daltons, and the weight percentage of the A blockis between 50.1% to 83%. The polyethylene glycol (PEG), a PEGderivative, or a mixtures of PEG and a PEG derivative, preferably have amolecular weight of 150 to 1100 Daltons. The composition can beadministered as is or after being be dissolved or rapidly reconstitutedin an aqueous vehicle to afford a homogeneous solution or uniformcolloidal system. After the administration, the water solublebiodegradable block copolymer may or may not form a gel, depending onmolecular weight and hydrophobic block weight percentage of the blockcopolymer contained in the composition.

[0017] Another embodiment of the present invention is a liquidcomposition comprising 1) one or more biodegradable block copolymer drugcarriers comprising A-B, A-B-A or B-A-B block copolymers, wherein the Ablock is a biodegradable polyester or poly(ortho ester) and the B blockis polyethylene glycol (PEG), and 2) a liquid polyethylene glycol (PEG),a PEG derivative, or a mixtures of PEG and a PEG derivative; wherein thebiodegradable block copolymer is insoluble in an aqueous solution butsoluble in the PEG and/or PEG derivatives. Preferably, the waterinsoluble biodegradable block copolymer drug carriers have a totalmolecular weight of 1000 to 10,000 Daltons, and the weight percentage ofthe A block is between 20% to 99%. The liquid polyethylene glycol (PEG),a PEG derivative, or a mixtures of PEG and a PEG derivative, preferablyhave a molecular weight of 150 to 1100 Daltons. The liquid compositionis a homogeneous solution or uniform colloidal system and can beadministered directly to a warm blooded animal. After theadministration, the liquid composition forms a drug containing depot andslowly releases the active substance over a prolonged period of time andis then decomposed into materials harmless to the human body andexcreted.

[0018] Examples of suitable biodegradable water soluble drug carriersincludes biodegradable ABA- or BAB-type triblock copolymers, or AB-typediblock copolymers based on biodegradable polyester or poly(ortho ester)A-blocks and hydrophilic B polymer block(s) consisting of polyethyleneglycol (PEG). The biodegradable polyester are synthesized from monomersselected from the group consisting of D,L-lactide, D-lactide, L-lactide,D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid,ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoic acid,γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone, δ-hydroxyvaleric acid, hydroxybutyric acids, malic acid, and copolymers thereof.

[0019] Polyethylene glycol (PEG) is also sometimes referred to aspoly(ethylene oxide) (PEO) or poly(oxyethylene) when incorporated into ablock copolymer, and the terms can be used interchangeably for thepurposes of this invention.

[0020] In the case where the A-block(s) are PLA/PLGA polyester, thelactate content is between about 20 to 100 mole percent, preferablybetween about 50 to 100 mole percent. The glycolate content is betweenabout 0 and 80 mole percent, preferably between about 0 to 50 molepercent. Or, stated differently, when the A-block is PLGA the glycolatecontent is between about 1 and 80 mole percent and preferably betweenabout 1 and 50 mole percent and the lactate content is between 20 and 99mole percent and preferably between 50 and 99 mole percent.

[0021] The PEG derivative suitable in the present invention refers to anester or ortho ester derivatized PEG having a molecular weight of 150 to1100. Preferably, the ester derivatized PEG is a PEG derivatized from amember selected from the group consisting of D,L-lactide, D-lactide,L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide,glycolic acid, ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoicacid, γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone,δ-hydroxy valeric acid, hydroxybutyric acids, malic acid, and mixturesthereof. The PEG derivative can also be a member represented byR¹—CO—O—(CH₂—CH₂—O)_(n)—CO—R² or R¹—O—(CH₂—CH₂—O)_(n)—R² wherein R¹ andR² are independently members selected from the group consisting of H andC₁ to C₁₀ alkyl and n is an integer between 3 and 20.

[0022] The biodegradable block copolymer drug carriers suitable for thepresent invention can form homogeneous, free-flowing solutions oruniform colloidal systems in an aqueous vehicle or in the liquid PEG orPEG derivatives or mixtures thereof. Homogeneous solutions and uniformcolloidal systems of the drug delivery compositions includes all flowingforms of the compositions of the present invention, with or withoutwater, drug(s), and any additives or excipients as necessary to prepareformulations that are pharmaceutically and therapeutically useful. Thedrug may be present as either a true solution or in a colloidal statesuch as emulsion or a suspension. All forms can act to facilitateadministration of the drug and enhance the therapeutic effect. Suchtherapeutic effects may be optimized by controlling the copolymermolecular weights, compositions, and the relative ratios of thehydrophilic and hydrophobic blocks, ratios of drug to copolymer, ratiosof copolymer to PEG and/or PEG derivatives, and both drug and copolymerconcentrations in the final administered dosage form. Additionaladvantages of this invention will become apparent from the followingdetailed description of the various embodiments.

DETAILED DESCRIPTION OF THE INVENTION

[0023] This invention is not limited to the particular configurations,process steps, and materials disclosed herein, as such configurations,process steps, and materials may vary somewhat. It is also to beunderstood that the terminology employed herein is used for the purposeof describing particular embodiments only, and is not intended to belimiting since the scope of the present invention will be limited onlyby the appended claims and equivalents thereof.

[0024] In this specification and the appended claims, the singular forms“a,” “an,” and “the” include plural references unless the contextclearly dictates otherwise. Thus, for example, reference to acomposition for delivering “a drug” includes reference to one, two, ormore drugs. In describing and claiming the present invention, thefollowing terminology will be used in accordance with the definitionsset out below.

[0025] “Effective amount” means an amount of a drug, biologically activeagent or pharmacologically active agent that provides the desired localor systemic effect.

[0026] “Copolymer solution”, when used in reference to a biodegradableblock copolymer contained in such a solution, shall mean an aqueouscomposition having such biodegradable block copolymer drug carriereither dissolved to form a homogeneous solution or uniform colloidalsystem.

[0027] “Drug formulations”, “drug delivery compositions”, and the like,shall mean the combination of drug, the block copolymer drug carrier,and PEG, PEG derivatives, or mixtures of PEG and PEG derivatives. Theyshall include all combinations of the drug with the block copolymer andPEG, PEG derivatives, or mixtures thereof.

[0028] “Aqueous solution”, “aqueous vehicle” and the like, shall includewater without additives or aqueous solutions containing additives orexcipients such as pH buffers, components for tonicity adjustment,antioxidants, preservatives, drug stabilizers, etc., as commonly used inthe preparation of pharmaceutical formulations.

[0029] “Drug solution”, “solubilized drug”, “dissolved drug” and allother terms that refer to the drug in a solution or dissolved stateincludes the drug being present as either a homogeneous solution,micellar solution, or in a colloidal state such as emulsion or asuspension. Thus, solubilized drugs and drug solutions include allflowing forms of the drug delivery compositions of the presentinvention. All forms can act to facilitate administration of the drugand enhance the therapeutic effect.

[0030] “Reconstitution” refers to mixing of biodegradable blockcopolymer drug carriers and the PEG, PEG derivatives or mixtures thereofwith an aqueous solvent system to create a homogenous solution oruniform colloidal system. This is in addition to the more traditionaldefinition of reconstitution where drug and excipients are mixed with asolvent, usually aqueous, immediately before administration.

[0031] “Enhanced reconstitution properties” refers to properties thatenable rapid reconstitution of block copolymeric drug carriers to thefinal physical state as either a true solution or a uniform colloidalsystem. The reconstitution process occurs within a short period of time,typically between 0.01 minutes to 120 minutes, preferably within 0.01minutes to 60 minutes, and most preferably within 0.01 minutes to 30minutes.

[0032] “Reverse thermal gelation” is the phenomenon whereby an aqueoussolution of a block copolymer spontaneously increases in viscosity, andin many instances transforms into a semisolid gel, as the temperature ofthe polymer solution is increased above the gelation temperature of theblock copolymer solution. For the purpose of the invention, the term gelincludes both the semisolid gel state and the high viscosity state thatexists above the gelation temperature. When cooled below the gelationtemperature the gel spontaneously reverses to reform the lower viscositypolymer solution. This cycling between the solution and the gel may berepeated indefinitely because the sol/gel transition does not involveany change in the chemical composition of the polymer solution. Allinteractions to create the gel are physical in nature and do not involvethe formation or breaking of covalent bonds.

[0033] “Administration” is the means by which drug formulations arepresented to humans and other warm-blooded animals in effective amounts,and includes all routes for dosing or administering drugs, whetherself-administered or administered by medical practitioners.

[0034] “Parenteral” shall mean administration by means other thanthrough the digestive tract such as by intramuscular, intraperitoneal,intra-abdominal, subcutaneous, intrathecal, intrapleural, intravenousand intraarterial means.

[0035] “Depot” means a localized site in the body containingconcentrated active agents or drugs. Examples of formulations that formdepots are gels, implants, microspheres, matrices, particles, etc.

[0036] “Biodegradable” means that the block copolymer or oligomer canchemically break down or degrade within the body to form nontoxiccomponents. The rate of degradation can be the same or different fromthe rate of drug release.

[0037] “Drug” shall mean any organic or inorganic compound or substancehaving biological or pharmacological activity that can be adapted orused for a therapeutic purpose.

[0038] “Peptide,” “polypeptide,” “oligopeptide” and “protein” shall beused interchangeably when referring to peptide or protein drugs andshall not be limited as to any particular molecular weight, peptidesequence or length, field of bioactivity or therapeutic use unlessspecifically stated.

[0039] “PLGA” shall mean a copolymer or copolymer radicals derived fromthe condensation copolymerization of lactic acid and glycolic acid, or,by the ring opening copolymerization of lactide and glycolide. The termslactic acid and lactate are used interchangeably; glycolic acid andglycolate are also used interchangeably.

[0040] “PLA” shall mean a polymer derived from the condensation oflactic acid or by the ring opening polymerization of lactide.

[0041] “PGA” shall mean a polymer derived from the condensation ofglycolic acid or by the ring opening polymerization of glycolide.

[0042] “Biodegradable polyester or poly(ortho ester)s” refers to anybiodegradable polyester or poly(ortho ester)s. The polyesters arepreferably synthesized from monomers selected from the group consistingof D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid,L-lactic acid, glycolide, glycolic acid, ε-caprolactone,1,4-dioxan-2-one, ε-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxybutyric acid, δ-valerolactone, δ-hydroxy valeric acid, hydroxybutyricacid, malic acid, and mixtures thereof.

[0043] “Ortho ester” is a carbon which single bonded to three oxygenatoms covalently.

[0044] The present invention is based on the discovery of PEG, PEGderivatives or mixtures thereof that can, in minutes, efficientlyaccelerate the dissolution of the biodegradable block copolymer drugcarriers into an aqueous medium. The liquid PEG, PEG derivatives ormixtures thereof of the present invention can also dissolve thebiodegradable block copolymer drug carriers to create a flowable drugdelivery composition. The “PEG, PEG derivatives or mixtures thereof” ofthe present invention have a weight averaged molecular weight of 150 to1100. The PEG derivative suitable in the present invention refers to anester or ortho ester derivatized PEG having a molecular weight of 150 to1100. Preferably, the ester derivatized PEG is a PEG derivatized from amember selected from the group consisting of D,L-lactide, D-lactide,L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide,glycolic acid, ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoicacid, γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone,δ-hydroxy valeric acid, hydroxybutyric acids, malic acid, and mixturesthereof. The PEG derivative can also be a member represented byR¹—CO—O—(CH₂—CH₂—O)_(n)—CO—R² or R¹—O—(CH₂—CH₂—O)_(n)—R² wherein R¹ andR² are independently members selected from the group consisting of H andC₁ to C₁₀ alkyl and n is an integer between 3 and 20.

[0045] The biodegradable block copolymer drug carriers of the presentinvention may be soluble in an aqueous solution, in the liquid PEG, PEGderivatives or mixtures thereof, or both. Examples of some of thesebiodegradable block copolymer drug carriers are disclosed in U.S. Pat.No. 6,201,072 and pending U.S. patent application Ser. Nos. 09/559,799;09/971,074, filed on Oct. 3, 2001 and Ser No. 09/971,082 filed on Oct.3, 2001, hereby fully incorporated by reference. The composition can beadministered as is or after being dissolved or rapidly reconstituted inan aqueous vehicle to afford a homogeneous solution or uniform colloidalsystem. After the administration, the water soluble biodegradable blockcopolymer may or may not form a gel, depending on molecular weight andhydrophobic block weight percentage of the block copolymer contained inthe composition. Water soluble biodegradable block copolymers areprepared wherein the hydrophilic B-block(s) make up about 17 to 49.9% byweight of the copolymer and the hydrophobic A-block or blocks make upabout 50.1 to 83% by weight of the copolymer. The weight ratio of thewater soluble biodegradable block copolymer drug carrier and the PEG,PEG derivatives, or mixtures of PEG and PEG derivatives, is between 5:1and 1:99. This composition can be administered as is or after beingquickly reconstituted in water or an aqueous solution and form a polymersolution comprising the composition of the present invention in water orthe aqueous solution at a weight ratio between 2:1 and 1:10000.

[0046] Alternatively, the biodegradable block copolymer may be insolublein an aqueous solution but is soluble in the liquid polyethylene glycol,PEG derivatives or mixtures thereof. In this case, the liquidcomposition is a homogeneous solution or uniform colloidal system andcan be administered directly to a warm blooded animal. After theadministration, the liquid composition forms a drug containing depot andslowly releases the active substance over a prolonged period of time andis then decomposed into materials harmless to the human body andexcreted. In the liquid composition of the present invention, the weightratio of the biodegradable block copolymer to the PEG, PEG derivativesor mixtures thereof is preferably within the range of 5:1 to 1:99, andmore preferably within the range of 2:1 to 1:99 and most preferablywithin the range of 1:2 to 1:5.

[0047] In one embodiment, the biodegradable drug carrier comprisesABA-type or BAB-type triblock copolymers, AB-type diblock copolymers ormixtures thereof, where the A-blocks are relatively hydrophobic andcomprises a biodegradable polyester or poly(ortho ester), and theB-blocks are relatively hydrophilic and comprises polyethylene glycol(PEG), said copolymer having a hydrophobic content of between 50.1 to83% by weight and hydrophilic content of between 17 to 49.9% by weight,and an overall block copolymer molecular weight of between 2000 and8000. The drug carriers exhibit water solubility at temperatures belownormal mammalian body temperatures and undergoes reversible thermalgelation to then exist as a gel at temperatures equal to physiologicalmammalian body temperatures.

[0048] In another embodiment, the biodegradable drug carrier is anABA-type, BAB-type, or AB-type block copolymer, or mixtures thereof,where the A-blocks are relatively hydrophobic and comprises abiodegradable polyester or poly(ortho ester), and the B-blocks arerelatively hydrophilic and comprises polyethylene glycol (PEG), saidblock copolymer having a hydrophobic content of between 50.1 to 65% byweight and a hydrophilic content of between 35 to 49.9% by weight, andan overall block copolymer weight-averaged molecular weight of between2400 and 4999. The drug carriers are water soluble and capable ofenhancing the solubility of drugs, hydrophobic drugs in particular, inwater, to form a drug solution.

[0049] In still another embodiment, the polymeric drug carrier comprisesbiodegradable polyester or poly(ortho ester) oligomers, and particularlyPLA/PLGA oligomers having a weight averaged molecular weight of between400 and 10,000, mixed with biodegradable ABA-type or BAB-type triblockcopolymers, or AB-type diblock copolymers having a weight averagedmolecular weight of between 2400 and 4999. The block copolymers have50.1 to 65% by weight of the hydrophobic A block(s) comprisingbiodegradable polyester or poly(ortho ester)s and 35 to 49.9% by weightof the hydrophilic B block(s) consisting of polyethylene glycol (PEG).

[0050] The PEG, PEG derivatives or mixtures thereof used in the presentinvention dissolves or uniformly mixes with the biodegradable blockcopolymer and so reduces the viscosity and increases the fluidity of thecomposition. The compositions of the present invention are flowableliquids or can be easily formulated with an aqueous vehicle to afford afluid homogeneous solution or uniform colloidal system. In the casesthat the block copolymeric drug carrier is insoluble in an aqueousvehicle but soluble in the liquid PEG and/or PEG derivatives, when incontact with water or body fluids, the block copolymer forms a drugdepot. In cases that the block copolymeric drug carrier is soluble in anaqueous vehicle and miscible with the PEG and/or PEG derivatives, thecomposition can be easily administered as is or reconstituted with anaqueous vehicle. After the administration, the block copolymer drugcarrier may or may not form a drug depot. Therefore, the liquid PEG, PEGderivative or mixtures thereof of the present invention should be amaterial that does not cause loss of activity of the physiologicallyactive substance.

[0051] For purposes of disclosing molecular weight parameters, allreported molecular weight values are based on measurements by ¹H-NMR orGPC (gel permeation chromatography) analytical techniques. The reportedweight averaged molecular weights and number averaged molecular weightswere determined by GPC and ¹H-NMR, respectively. The reportedlactide/glycolide ratios were calculated from ¹H-NMR data. GPC analysiswas performed on a Styragel HR-3 column, or equivalent, calibrated withPEG standards using RI detection and chloroform as the eluent, or on acombination of Phenogel, mixed bed, and 500 Å columns calibrated withPEG standards using RI detection and tetrahydrofuran as the eluent forthe ABA and BAB triblock copolymers.

[0052] ABA-type and BAB-type triblock copolymers, and AB-type diblockcopolymers may be synthesized by ring opening polymerization, orcondensation polymerization. Additionally, the B-blocks may, in certaininstances, be coupled to the A-blocks by ester or urethane links and thelike. Condensation polymerization and ring opening polymerizationprocedures may be utilized as may the coupling of a monofunctionalhydrophilic B block to either end of a difunctional hydrophobic A blockin the presence of coupling agents such as isocyanates. Furthermore,coupling reactions may follow activation of functional groups withactivating agents, such as carbonyl diimidazole, succinic anhydride,N-hydroxy succinimide, p-nitrophenyl chloroformate and the like.

[0053] The hydrophilic B-block is formed from PEG of an appropriatemolecular weight. PEG was chosen as the hydrophilic B-block because ofits unique biocompatibility, nontoxic properties, hydrophilicity,solubilization properties, and rapid clearance from a patient's body.The hydrophobic A-blocks are utilized because of their biodegradable,biocompatible, and solubilization properties. The in vitro and in vivodegradation of hydrophobic, biodegradable polyester or poly(ortho ester)A-blocks are well understood and the degradation products are readilymetabolized and/or eliminated from the patient's body.

[0054] Drugs that may be incorporated with the drug deliverycompositions of the present invention can be any bioactive agent, butparticular advantage is achieved with bioactive agents having limitedsolubility or dispersibility in an aqueous or hydrophilic environment,or any bioactive agent that requires enhanced solubility ordispersibility. Without limiting the scope of the present invention,suitable drugs include those drugs presented in current edition ofGoodman and Gilman's “The Pharmacological Basis of Therapeutics” or thecurrent edition of The Merck Index. Both volumes list drugs suitable fornumerous types of therapeutic applications, including drugs in thefollowing categories:drugs acting at synaptic and neuroeffectorjunctional sites, drugs acting on the central nervous system, drugs thatinfluence inflammatory responses, drugs that affect the composition ofbody fluids, drugs affecting renal function and electrolyte metabolism,cardiovascular drugs, drugs affecting gastrointestinal function, drugsaffecting uterine motility, chemotherapeutic agents for parasiticinfections, chemotherapeutic agents for microbial diseases,antineoplastic agents, immunosuppressive agents, drugs affecting theblood and blood-forming organs, hormones and hormone antagonists,dermatological agents, heavy metal antagonists, vitamins and nutrients,vaccines, oligonucleotides and gene therapies.

[0055] Incorporating one or more drugs mentioned in the above categorieswith the compositions of the present invention to form drug deliverycompositions which can be dissolved or easily reconstituted to form anaqueous solution or uniform colloidal system can be achieved by simplyadding the drug to the liquid composition or an aqueous solutions of thecompositions of the present invention, or by mixing the drug with thecompositions of the present invention and thereafter adding water or anaqueous solution to form a solution or uniform colloidal system.

[0056] Mixtures of the compositions of the present invention withpeptide/protein drugs, and/or other types of drugs, may be prepared asflowable drug delivery formulations or formulations that may be easilyreconstituted in the form of a solution or dispersion. The flowableformulation is then administered parenterally, topically, transdermally,transmucosally, inhaled, or inserted into a cavity such as by ocular,vaginal, transurethral, rectal, nasal, oral, peroral, buccal, pulmonaryor aural administration to a patient. Many of the solubilized drugformulations prepared by implementing the present invention may bediluted in an i.v. bag or by other means, and administered to a patientfor an extended period, without precipitation of the drug. Due to thebiocompatibility of the materials and the free flowing nature of thesystem at physiological temperatures, this system will cause minimaltoxicity and minimal mechanical irritation to the surrounding tissue.

[0057] A distinct advantage to the compositions of this invention liesin the ability of PEG, PEG derivatives or mixtures thereof to reduce theviscosity of the biodegradable block copolymer drug carriers into a formthat is flowable liquid or can be quickly reconstitutable in water or anaqueous solution to form a solution or uniform colloidal system for drugdelivery. In one possible configuration, a dosage form comprised of asolution of the block copolymer drug carrier and a PEG, PEG derivativesor mixtures thereof that contains drug is administered to the body. Inanother possible configuration, the drug delivery composition of thepresent invention maybe quickly dissolved or reconstituted by usingwater or other aqueous solutions.

[0058] The only limitation as to how much drug can be dissolved ordispersed in the drug delivery composition of the present invention isone of functionality, namely, the drug:copolymer ratio may be increaseduntil the properties of the mixture are adversely affected to anunacceptable degree, or until the properties of the system are adverselyaffected to such a degree as to make administration of the systemunacceptably difficult. Generally speaking, it is anticipated that inmost instances where dissolution is desired, the drug will be present atbetween about 10⁻⁶ to about 100 percent by weight of the combined weightthe block copolymer drug carrier and the PEG, PEG derivatives ormixtures thereof, with ranges of between about 0.001% to 25% by weightbeing the most common. For example, having the drug present at 100% byweight of the combined weight of the block copolymer drug carrier andthe PEG, PEG derivatives or mixtures thereof means that the drug andcombined weight the block copolymer drug carrier and the PEG, PEGderivatives or mixtures thereof are present in equal amounts (i.e.,equal weights). Generally speaking, it is anticipated that in mostinstances where dispersion is desired, the upper drug:copolymer ratiocould substantially exceed the range noted above for dissolution. Theseranges of drug loading are illustrative and will include most drugs thatmay be utilized in the present invention. However, such ranges are notlimiting to the invention should drug loadings outside this range befunctional and effective.

[0059] The present invention thus provides compositions comprisingbiodegradable block copolymer drug carriers and PEG, PEG derivatives ormixtures thereof that are flowable liquids or can be rapidlyreconstituted in an aqueous vehicle to afford useful forms that may beeither homogeneous true solutions or uniform colloidal systems. The drugsolution formed with the drug delivery compositions of the presentinvention has desirable physical stability, therapeutic efficacy, andtoxicology. The PEG, PEG derivatives or mixtures thereof of the presentinvention can be used for water soluble or water insoluble blockcopolymeric drug carriers, particularly for biodegradable di- ortriblock copolymers that have reverse gelation properties and/orpolymers that can enhance the solubility of drugs, especiallyhydrophobic drugs.

[0060] The following are examples that illustrate preferred embodimentsof the invention but are intended as being representative only.

EXAMPLE 1

[0061] PEG-300 (107.6 g) was placed in a 250-mL round bottom flask anddried under vacuum (0.2 torr, 90° C.) for 3 hours. D,L-Lactide (33.4 g)and glycolide (9.0 g) was added and the head-space was replaced by driednitrogen. The mixture was brought to 135° C. and the reaction wasinitiated by adding stannous octoate (20 mg) via a dry syringe. Thereaction mixture was allowed to stir under dry nitrogen at 155° C. forfour additional hours. Residual monomers were removed under vacuum (0.2torr, 90° C., 2 hr). The resulting PEG derivative(D1) was a clearfree-flowing liquid.

EXAMPLE 2

[0062] Following the procedure described in Example 1, the following PEGderivatives were prepared. TABLE 1 PEG derivatives synthesized by themethod described in Example 1 PEG weight Glycolide D,L-Lactide ID PEG(gram) (gram) (gram) D2 PEG200NF 30.0 7.62 28.38 D3 PEG200NF 33.33 5.6421.02 D4 PEG300NF 57.14 4.84 18.02 D5 PEG600NF 50.0 4.23 15.75 D6Triethylene 50.0 4.23 15.77 glycol D7 PEG300NF 50.25 19.75 — D8 PEG300NF86.15 24.67 9.19 D9 PEG300NF 100.5 — 39.5

EXAMPLE 3

[0063] PEG-300 (40 g) was placed in a 250-mL round bottom flask.Moisture was removed by drying under vacuum (0.2 torr) at 90° C. for 3hours. Acetic anhydride (30 g) was added and the reaction mixture wasbrought to reflux under nitrogen over 48 hours. Excess acetic anhydridewas removed by vacuum distillation at 100° C. for 24 hours. Theresulting PEG derivative(D10) was a clear, free-flowing liquid.

EXAMPLE 4

[0064] This example illustrates the synthesis of the ABA-type triblockcopolymer PLGA-PEG-PLGA by ring opening copolymerization.

[0065] PEG 1000 NF (65.3 g) and PEG 1450 NF (261 g) was dried undervacuum (1 mmHg) at 130° C. for 5 hours. D,L-Lactide (531.12 g) andglycolide (142.6 g) were added to the flask and heated to 155° C. toafford a homogenous solution. Polymerization was initiated by theaddition of 250 mg stannous octoate to the reaction mixture. Aftermaintaining the reaction for five hours at 145° C., the reaction wasstopped and the flask was cooled to room temperature. Unreacted lactideand glycolide were removed by vacuum distillation. The resultingPLGA-PEG-PLGA copolymer mixture(ABA 1) had a weight averaged molecularweight (Mw) of 4255 as measured by GPC. This triblock copolymer mixtureis water soluble at room temperature. A 23% by weight aqueous solutionof this triblock copolymer mixture had a gel temperature between 30° C.and 37° C.

EXAMPLE 5

[0066] Using the procedure described in Example 4, the followingcopolymers or copolymer mixtures were synthesized: TABLE 2 Copolymerssynthesized using the procedure described in Example 3 Block LA/GA PEG1PEG2 PEG1/PEG2 Copolymer Molar Ratio MW MW wt Ratio MW (Dalton) RemarksPLG-PEG-PLG 75/25 1000 — 100/0  4250 Water (ABA 2) soluble PLG-PEG-PLG75/25 1450 — 100/0  3950 Water (ABA 3) soluble PLA-PEG-PLA 100/0  10001450 10/90 3980 Water (ABA 4) soluble PLG-PEG-PLG 75/25 1450 — 100/0 7540 Water (ABA 5) insoluble PLA-PE-PLA 100/0  1000  600 80/20 6500Water (ABA 6) insoluble

EXAMPLE 6

[0067] AB diblock copolymer was synthesized by placing 25.7 g of PEG-Me(Mw: 2000) in a 250 mL 3-neck round bottom reaction flask. Water wasremoved by heating in an oil bath (155° C.) under vacuum (0.5 torr) for3 hours. The reaction flask was then raised out of the oil bath and thevacuum was released.

[0068] D,L-Lactide (32.0 g) was weighed and added to the reaction flask.The headspace was replaced with dry nitrogen by repeated evacuation andflushing with dry nitrogen 5 times.

[0069] The flask was then lowered and immersed in a 155° C. oil bath.Once the content was melted and the internal temperature reached 150°C., 2 drops (200 ppm) of stannous 2-ethylhexanoate was added to initiatethe polymerization. The reaction mixture was stirred using an overheadstirrer for 8 hours at a rate of 100-200 rpm. The temperature was thenreduced to 140° C., and the residual monomer was removed under reducedpressure (<1 torr) over 1 hour. The residue is a translucent, off-whitesolid having a molecular weight of 5450.

[0070] One gram of the diblock copolymer was added to 4 grams of PEGderivative (D 10) to afford a clear and free flowing liquid. Uponaddition of the mixture to 37° C. water, the mixture turned cloudy dueto apparent precipitation of the water insoluble diblock copolymericcomponent.

EXAMPLE 7

[0071] Me-PEG (MW 550; 48.6 g) was transferred into a 250 mL 3-neckround bottom reaction flask. The oil bath was heated to 100° C. Themolten PEG-Me was stirred under vacuum for 5 hours to remove water. Thereaction flask was then raised outside of the oil bath and the vacuumwas released. D,L-Lactide (97.68 g) and glycolide (26.47 g) were weighedand added the reaction flask. The headspace was replaced with drynitrogen. The flask was then immersed into a 155° C. oil bath. Once theD,L-lactide was melted and the temperature inside the reaction flaskreached 150° C., 2 drops (200 ppm) of stannous 2-ethylhexanoate wasadded to the reaction flask. The reaction was stirred continuously for 8hours at a rate of 100-150 rpm.

[0072] The oil bath temperature was reduced to 140° C. and the reactionflask was attached to vacuum (<1 torr) for an hour to remove residualmonomer. The diblock copolymer had honey-like consistency with molecularweight of 2010. The residue (145 g) was added to 1,6-diisocynatohexane(6.06 g) via an oven dried syringe and the reaction mixture was allowedto stir at 140° C. for 2 additional hours. The residue was purified bydissolving the polymer in water and precipitation at 70° C. Water wasremoved by lyophilization and the residual BAB triblock copolymer had amolecular weight of 4250.

[0073] One gram of the polymer was dissolved in 4 gram of PEG derivative(D 4) and the mixture was added to 25 mL of warm water (37° C.) via a24-G needle. Upon addition of the mixture to 37° C. water, the mixtureturned cloudy due to apparent precipitation of the water insolublediblock copolymeric component.

EXAMPLE 8

[0074] The use PEG derivatives for reconstitution are illustrated inthis example.

[0075] The PEG derivative(1.5 g) prepared from Example 1 were added to 1gram of PLGA-PEG-PLGA triblock copolymer prepared from Example 4. Thetwo components were intimately mixed into a homogeneous mixture. To themixture, water for injection (5 g) was added shaken. The mixture took 1minute to reconstitute. The resulting aqueous solution had a gelationtemperature at 30° C. and 37° C.

[0076] Zinc insulin (5 mg) was reconstituted with 5 mL of the aqueoussolution and the solution was injected into 37° C. water. The solutionrapidly gelled.

EXAMPLE 9

[0077] Zn-insulin (5 mg) is suspended a mixture composed of a triblockcopolymer (ABA 6; 1 g) dissolved in 6 g of PEG derivative (D 2). Themixture is a free-flowing liquid. One mL of the suspension is injectedinto warm water (25 mL; 37° C.). Upon addition of the mixture to 37° C.water, the mixture turned cloudy due to apparent precipitation of thewater insoluble triblock copolymeric component.

EXAMPLE 10

[0078] The PEG derivatives (D6; 4 g) were added to 1 gram ofPLGA-PEG-PLGA triblock copolymer (ABA3). Also added to the mixture was50 mg of paclitaxel. The mixture was intimately mixed into a homogeneousmixture at ca. 40° C. for ca. 20 minutes. The mixture was a clear freeflowing liquid. One gram of the mixture was added to a beaker containing25 mL of warm water (37° C.). The mixture apparently dissolved rapidlyto afford a clear solution or uniform colloid.

EXAMPLE 11

[0079] The PEG derivative(3 g) from Example 1 were intimately mixed with1 gram of PLGA-PEG-PLGA triblock copolymer (ABA3) and 0.08 g ofpoly(D,L-lactate-co-glycolate) (MW 1200) into a homogeneous mixture.Paclitaxel (75 mg) was dissolved into the mixture with gentle stirringat ca. 45° C. After equilibrated to ambient temperature, water forinjection (5 g) was added and the mixture was shaken. The mixtureapparently dissolved rapidly to afford a clear solution or uniformcolloid.

EXAMPLE 12

[0080] This example illustrate the synthesis of poly(ortho ester) ABdiblock copolymer.

[0081] Dried 1,4-cyclohexanedimethanol (2.6 g), PEG 2000 methyl ether (4g) is heated at 70° C. with DETOSU(3,9-bis(ethylidene)-2,4,8,10-tetraoxaspiro[5,5]undecane; 4.35 g) indried 1,4-dioxane (100 mL) over 8 hour. The solvent is removed undervacuum (0.5 torr; 70° C.) over 40 hours. The resulting poly(ortho ester)AB diblock copolymer is a transparent copolymer.

EXAMPLE 13

[0082] This example illustrates the synthesis of PEG ortho esterderivative. PEG 300 (25.0 g) is heated in a round bottomed flask undervacuum at 90° C. for 3 hours to remove residual water. Molten DETOSU(3,9-bis(ethylidine)-2,4,8,10-tetraoxaspiro[5,5]undecane) (4.0 grams)isadded to the flask through an oven dried syringe. The mixture is allowedto heat at 90° C. over 5 hours. The resulting PEG ortho ester derivativeis a clear liquid.

EXAMPLE 14

[0083] This example illustrates the use of PEG ortho ester derivative.Paclitaxel (50 mg) is dissolved with mild heating into a mixture of PEGderivative (15 g) synthesized in Example 13 and an AB diblock poly(orthoester) copolymer (3 g) prepared in Example 12. The resulting mixture isa clear liquid. Upon addition of the mixture to 37° C. water, themixture turned cloudy due to apparent precipitation of the waterinsoluble diblock copolymeric component.

[0084] The above description will enable one skilled in the art to makea composition comprising biodegradable block copolymer drug carriers andPEG, PEG derivatives, or a mixtures thereof, said composition is aflowable liquid or can be rapidly reconstituted in an aqueous vehicle tohomogeneous solutions or uniform colloidal systems. Although the drugdelivery compositions are described to show the functionality of thecompositions of the present invention, these descriptions are notintended to be an exhaustive statement of all drug carriers that can berendered soluble and/or constitutable by the compositions of the presentinvention. Certainly, numerous other drug carriers or drugs from variouscategories of therapeutic agents are well suited for the drug deliverycompositions described in this invention. It will be immediatelyapparent to one skilled in the art which various modifications may bemade without departing from the scope of the invention that is limitedonly by the following claims and their functional equivalents.

We claim:
 1. A composition comprising: 1) one or more biodegradableblock copolymer drug carriers comprising A-B, A-B-A or B-A-B blockcopolymers having a total weight average molecular weight of 1000 to100,000 Daltons, wherein the A block is a biodegradable polyester orpoly(ortho ester) and the B block is polyethylene glycol(PEG), and theweight percentage of the A block is between 20% to 99% and the weightpercentage of the B block is between 1% to 80%; and 2) a liquidpolyethylene glycol(PEG), a PEG derivative, or a mixture of PEG and aPEG derivative, said PEG or PEG derivative having a molecular weight of150 to 1100 Daltons; wherein the biodegradable block copolymeric drugcarrier is soluble in the liquid PEG, PEG derivatives, or mixtures ofPEG and PEG derivatives.
 2. The composition according to claim 1 whereinthe PEG derivative is an ester derivatized PEG wherein the PEG isderivatized from a member selected from the group consisting ofD,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid,L-lactic acid, glycolide, glycolic acid, ε-caprolactone,1,4-dioxan-2-one, ε-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxybutyric acid, δ-valerolactone, δ-hydroxy valeric acid, hydroxybutyricacids, malic acid, and mixtures thereof.
 3. The composition according toclaim 1 wherein the PEG derivative is an ortho ester derivatized PEG. 4.The composition according to claim 1 wherein the PEG derivative isrepresented by R¹—CO—O—(CH₂—CH₂—O)_(n)—CO—R² or R¹—O—(CH₂—CH₂—O)_(n)—R²wherein R¹ and R² are independently members selected from the groupconsisting of H and C₁ to C₁₀ alkyl and n is an integer between 3 and20.
 5. The composition according to claim 1 wherein the biodegradableblock copolymeric drug carrier further comprises a biodegradablepolyester or poly(ortho ester) oligomer having a weight averagemolecular weight of between 400 and 10,000 Daltons.
 6. The compositionaccording to claim 1 wherein the weight ratio of the biodegradable blockcopolymeric drug carrier and the PEG, PEG derivative or mixtures thereofis within the range of 5:1 to 1:99.
 7. The composition according toclaim 1 further comprising a drug.
 8. A composition comprising: 1) oneor more biodegradable block copolymer drug carriers comprising A-B,A-B-A or B-A-B block copolymers having a total weight average molecularweight of 2000 to 8000 Daltons, wherein the A block is a biodegradablepolyester or poly(ortho ester) and the B block is polyethyleneglycol(PEG), and the weight percentage of the A block is between 50.1%to 83% and the weight percentage of the B block is between 17% to 49.9%;and 2) a polyethylene glycol(PEG), a PEG derivative, or a mixtures ofPEG and a PEG derivative, said PEG or PEG derivative having a molecularweight of 150 to 1100 Daltons; and wherein at least one of thebiodegradable block copolymeric drug carriers is soluble in an aqueoussolution and miscible with the PEG, PEG derivatives, or mixturesthereof, and wherein said composition can be reconstituted in water oran aqueous solution to form a homogeneous solution or an uniformcolloidal system within 0.01 minutes to 180 minutes.
 9. The compositionaccording to claim 8 wherein the PEG derivative is an ester derivatizedPEG wherein the PEG is derivatized from a member selected from the groupconsisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid,D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε-caprolactone,1,4-dioxan-2-one, ε-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxybutyric acid, δ-valerolactone, δ-hydroxy valeric acid, hydroxybutyricacids, malic acid, and mixtures thereof.
 10. The composition accordingto claim 8 wherein the PEG derivative is an ortho ester derivatized PEG.11. The composition according to claim 8 wherein the PEG derivative isrepresented by R¹—O—O—(CH₂—CH₂—O)_(n)—CO—R² or R¹—O—(CH₂—CH₂—O)_(n)—R²wherein R¹ and R² are independently members selected from the groupconsisting of H and C₁ to C₁₀ alkyl and n is an integer between 3 and20.
 12. The composition according to claim 8 wherein the biodegradableblock copolymeric drug carrier further comprises a biodegradablepolyester or poly(ortho ester) oligomer having a weight averagemolecular weight of between 400 and 10,000 daltons.
 13. The compositionaccording to claim 8 wherein the weight ratio of the biodegradable blockcopolymeric drug carrier and the PEG, PEG derivative or mixtures thereofis within the range of 5:1 to 1:99.
 14. The composition according toclaim 8 further comprising a drug.
 15. A composition according to claim8, wherein the biodegradable ABA- or BAB-type tri-block copolymerscomprise: i) 51 to 83% by weight of a biodegradable, hydrophobic A blockcomprising a biodegradable polyester or poly(ortho ester), and ii) 17 to49% by weight of a hydrophilic B block comprising a polyethyleneglycol(PEG), and wherein the tri-block copolymers have a weight averagemolecular weight of between about 2000 to 4990 and possess reversethermal gelation properties.
 16. The composition according to claim 15wherein the PEG derivative is an ester derivatized PEG wherein the PEGis derivatized from a member selected from the group consisting ofD,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid,L-lactic acid, glycolide, glycolic acid, ε-caprolactone,1,4-dioxan-2-one, ε-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxybutyric acid, δ-valerolactone, δ-hydroxy valeric acid, hydroxybutyricacids, malic acid, and mixtures thereof.
 17. The composition accordingto claim 15 wherein the PEG derivative is an ortho ester derivatizedPEG.
 18. The composition according to claim 15 wherein the PEGderivative is represented by R¹—CO—O—(CH₂—CH₂—O)_(n)CO—R² orR¹—O—(CH₂—CH₂—O)_(n)—R² wherein R¹ and R² are independently membersselected from the group consisting of H and C₁ to C₁₀ alkyl and n is aninteger between 3 and
 20. 19. The composition according to claim 15wherein the weight ratio of the biodegradable block copolymeric drugcarrier and the PEG, PEG derivative or mixtures thereof is within therange of 5:1 to 1:99.
 20. The composition according to claim 15 furthercomprising a drug.
 21. A composition according to claim 8, wherein thebiodegradable ABA-type, BAB- or AB-type block copolymer comprising: i)50.1 to 65% by weight of a biodegradable, hydrophobic A block comprisinga biodegradable polyester or poly(ortho ester), and ii) 35 to 49.9% byweight of a hydrophilic B block comprising a polyethylene glycol (PEG),and wherein the block copolymer has a weight average molecular weight ofbetween 2400 to 4999 daltons, with the proviso that said blockcopolymer, when formed as an aqueous polymer solution, is a free flowingliquid at temperatures of between at least 35 to 42° C.
 22. Thecomposition according to claim 21 wherein the PEG derivative is an esterderivatized PEG, wherein the PEG is derivatized from a member selectedfrom the group consisting of D,L-lactide, D-lactide, L-lactide,D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid,ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoic acid,γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone, δ-hydroxyvaleric acid, hydroxybutyric acids, malic acid, and mixtures thereof.23. The composition according to claim 21 wherein the PEG derivative isan ortho ester derivatized PEG.
 24. The composition according to claim21 wherein the PEG derivative is represented byR¹—CO—O—(CH₂—CH₂—O)_(n)CO—R² or R¹—O—(CH₂—CH₂—O)_(n)R² wherein R¹ and R²are independently members selected from the group consisting of H and C₁to C₁₀ alkyl and n is an integer between 3 and
 20. 25. The compositionaccording to claim 21 wherein the biodegradable block copolymeric drugcarrier further comprises a biodegradable polyester or poly(ortho ester)oligomer having a weight average molecular weight of between 400 and10,000 daltons.
 26. The composition according to claim 21 wherein theweight ratio of the biodegradable block copolymeric drug carrier and thePEG, PEG derivative or mixtures thereof is within the range of 5:1 to1:99.
 27. The composition according to claim 21 further comprising adrug.
 28. A composition comprising: 1) one or more biodegradable blockcopolymer drug carriers comprising A-B, A-B-A or B-A-B block copolymershaving a total weight average molecular weight of 1000 to 100,000Daltons, wherein the A block is a biodegradable polyester or poly(orthoester) and the B block is polyethylene glycol(PEG), and the weightpercentage of the A block is between 20% to 99% and the weightpercentage of the B block is between 1% to 80%; and 2) a liquidpolyethylene glycol(PEG), a PEG derivative, or a mixtures of PEG and aPEG derivative, said PEG or PEG derivative having a molecular weight of150 to 1100 Daltons; wherein the biodegradable block copolymeric drugcarrier is water insoluble but is soluble in the liquid PEG, a PEGderivative, or a mixtures of PEG and a PEG derivative.
 29. Thecomposition according to claim 28 wherein the PEG derivative is an esterderivatized PEG, wherein the PEG is derivatized from a member selectedfrom the group consisting of D,L-lactide, D-lactide, L-lactide,D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid,ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoic acid,γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone, δ-hydroxyvaleric acid, hydroxybutyric acids, malic acid, and mixtures thereof.30. The composition according to claim 28 wherein the PEG derivative isan ortho ester derivatized PEG.
 31. The composition according to claim28 wherein the PEG derivative is represented byR¹—CO—O—(CH₂—CH₂—O)_(n)—CO—R² or R¹—O—(CH₂—CH₂—O)_(n)—R² wherein R¹ andR² are independently members selected from the group consisting of H andC₁ to C₁₀ alkyl wherein n is an integer between 3 and
 20. 32. Thecomposition according to claim 28 wherein the biodegradable blockcopolymeric drug carrier further comprises a biodegradable polyester orpoly(ortho ester) oligomer having a weight average molecular weight ofbetween 400 and 10,000 daltons.
 33. The composition according to claim28 wherein the weight ratio of the biodegradable block copolymeric drugcarrier and the PEG, PEG derivative or mixtures thereof is within therange of 5:1 to 1:99.
 34. The composition according to claim 28 furthercomprising a drug.
 35. A method of preparing an improved drug deliveryformulation comprising the steps of: A) providing a drug deliverycomposition according to one of the claims 1 to 7; and B) formulatingthe composition as an injectable liquid which is without water, ormixing water or mixing an aqueous solution with the composition to forma homogeneous aqueous solution or a uniform colloidal system.
 36. Themethod according to claim 35 wherein the ratio of the composition towater or aqueous solution is within the range of 2:1 to 1:10,000. 37.The method according to claim 35 wherein the composition can bereconstituted in water or an aqueous solution to form a homogeneoussolution or an uniform colloidal system within 0.01 minutes to 180minutes.
 38. A method of preparing an improved drug delivery formulationcomprising the steps of: A) providing a drug delivery compositionaccording to one of the claims 8 to 27; and B) formulating thecomposition as an injectable liquid which is without water, or mixingwater or mixing an aqueous solution with the composition to form ahomogeneous aqueous solution or a uniform colloidal system.
 39. Themethod according to claim 38 wherein the ratio of the composition towater or aqueous solution is within the range of 2:1 to 1:10,000. 40.The method according to claim 38 wherein the composition can bereconstituted in water or an aqueous solution to form a homogeneoussolution or an uniform colloidal system within 0.01 minutes to 180minutes.
 41. A method of preparing an improved drug delivery formulationcomprising the steps of: A) providing a drug delivery compositionaccording to one of the claims 28 to 34; and B) formulating thecomposition as an injectable liquid without adding water.